The human helicase and ATPase up-frameshift suppressor 1 (UPF1), traditionally known as a major player in several RNA quality control mechanisms, is emerging as a crucial caretaker of the stability of the genome. Work from my laboratory has provided insight into the function of UPF1 during DNA metabolism and has revealed that this versatile enzyme sustains the proper replication of telomeres, the protective structures located at the ends of linear eukaryotic chromosomes. We have supplied direct evidence that telomere replication is not completed in cells with compromised UPF1 function, leading to the accumulation of DNA damage and telomere abnormalities. We also have isolated a number of factors that physically interact with UPF1 and might represent molecular links between UPF1 and telomeres. In this paper, I re-evaluate the functions of UPF1 in maintaining the stability of telomeres and of the genome at large and suggest a model that explains how UPF1 might be recruited and function during telomere replication.